Myeloid/Lymphoid Neoplasms with FGFR1 Rearrangement

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editPREVIOUS EDITION
This page from the 4th edition of Haematolymphoid Tumours is being updated. See 5th edition Table of Contents.

Primary Author(s)*

Yanna Ding, MD PhD

Cancer Category/Type

Myeloid/lymphoid neoplasms

Cancer Sub-Classification / Subtype

Myeloid/lymphoid neoplasms with eosinophilia and gene rearrangement

Definition / Description of Disease

Myeloid/lymphoid neoplasms with FGFR1 rearrangement are a heterogenous group of aggressive neoplasms with translocations involving the fibroblast growth factor receptor 1(FGFR1) tyrosine kinase gene on chromosome 8p11-12[1]. The neoplastic cells derive from a pluripotent haematopoietic stem cell and may be immature or mature[2]. Cases can present as a myeloproliferative neoplasm or as acute myeloid leukaemia, T- or B-lymphoblastic leukaemia/lymphoma or mixed-phenotype acute leukaemia. T-cell lymphoblastic lymphoma/leukemia is common, frequently with eosinophilia, and subsequently rapidly transforms into acute myeloid leukaemia.

Coexistence of atypical chronic myeloid leukaemia, BCR-ABL1-negative, with t(8;19)(p11.2;q13.1) and KIT D816V-positive systemic mastocytosis with an associated haematological neoplasm has been reported [3].

Synonyms / Terminology

8p11 myeloproliferative syndrome (EMS)

8p11 stem cell syndrome

8p11 stem cell leukaemia/lymphoma syndrome

Haematopoietic stem cell neoplasm with FGFR1 abnormalities

Myeloid and lymphoid neoplasms with FGFR1 abnormalities [2]

Epidemiology / Prevalence

The median age at disease onset is 32 years, although it can occur within a wide age range of 3-84 years [4]. There is a moderate predominance of male with male-to-female ratio of 1.5:1, unlike in myeloid/lymphoid neoplasms with PDGFRA or PDGFRB rearrangement [2].

Clinical Features

Systemic symptoms are common, including fatigue, fever, weight loss and night sweats. Some patients can be asymptomatic. Patients often present with peripheral blood eosinophilia without basophilia [1]. Cases with lymphoma features present as lymph nodes involvement and mediastinal mass; cases with myeloproliferative features present as splenomegaly and hypermetabolism. Cases can also present as acute myeloid leukaemia or myeloid sarcoma [4] [5] [6]. Extranodal sites of disease include tonsil, lung, and breast in small subsets of patients [1].

Sites of Involvement

Bone marrow, peripheral blood, lymph nodes, liver and spleen are primarily involved. Lymphoblasts or myeloid cells infiltration results in lymphadenopathy [2].

Morphologic Features

Peripheral blood: Most cases have leukocytosis with increased neutrophils, bands, metamyelocytes, and myelocytes. Circulating blasts and eosinophilia are common. Monocytosis can be found. Hemoglobin levels have ranged from 6.3 to 21 g/dL and platelet counts have ranged from 8 to 546 × 109/L[1].

Bone marrow biopsy: often hypercellularity due to increased granulocytic precursors and eosinophilia. Hypocellular cases also exist. Many cases were interpreted as myeloid hyperplasia or myeloproliferative neoplasm, including chronic myelogenous leukemia, atypical chronic myeloid leukemia, or chronic myelomonocytic leukemia. Primary diagnoses also include myelodysplastic syndrome, myelodysplastic syndrome/myeloproliferative neoplasm due to dysplasia. 16% of the cases may have 20% or more blasts, in the range of acute leukemia with blasts of a myeloid lineage or bilineal lineage in two thirds of the cases, and of pure immature lymphoid lineage in one third of the cases [7]. Lymphoblastic lymphoma is more commonly seen in patients with t(8;13)[3].

Lymph node biopsy: For patients who did undergo lymph node biopsy, 79% had T-lymphoblastic lymphoma and 21% myeloid sarcoma. Lymph nodes are infiltreated by small- or mediumsized lymphoblasts with fine or “dusty” chromatin and minimal cytoplasm. Eosinophils are frequently admixed with the lymphoblasts. Subtle myeloid component can be found in perivascular area. lymphoblastic component can be immunoreactive to TdT (terminal deoxynucleotidyl transferase), CD1a and pan-T-cell antigens while the subtle myeloid component can be positive for myeloperoxidase, CD15, CD68, CD117, lysozyme, or other myeloid-associated antigens[8] .

Basophilia can be found in cases with BCR-FGFR1 fusion [9], and in cases with t(1;8)(q31.1;p11.2)/TRP-FGFR1 fusion [10]. Polycythaemia vera has been reported in cases with t(6;8)(q27;p11.2)/FGFR1OP-FGFR1 fusion [11].

Immunophenotype

Immunophenotypic analysis is not helpful in chronic phase disease. However, in lymphoblastic leukemia/lymphoma and in acute myeloid transformation, immunophenotypic analysis is important to distinguish the lineage origins, such as B- or T- lineage, or myeloid lineage [2]. Please refer to the above section "Morphologic Features".

Chromosomal Rearrangements (Gene Fusions)

Various translocations with an 8p11 breakpoint are found. Depending on the partners, a variety of fusion genes with part of FGFR1 from 8p11 can be formed, encoding aberrant tyrosine kinases. Note: Some precise mapping has positioned FGFR1 locus to 8p12, instead of 8p11 [12].

Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Prevalence
t(8;13)(p11.2;q12.1) ZMYM2-FGFR1 Most common, around 40% [13][14][15][16][17][1]
t(8;9)(p11.2;q33.2) CNTRL-FGFR1 Around 17% [1][18]
t(6;8)(q27;p11.2) FGFR1OP-FGFR1 Around 9% [1] [19]
t(8;22)(p11.2;q11.2) BCR-FGFR1 At least eight cases[20][21][22][23][24]
t(7;8)(q33;p11.2) TRIM24-FGFR1 At least two cases [25][26]
t(8;17)(p11.2;q23) MYO18A-FGFR1 At least one case[27]
t(8;19)(p11.2;q13.3) HERVK-FGFR1 At least one case [28][29]
ins(12;8)(p11.2;p11.2p22) FGFR1OP2-FGFR1 At least two cases [26][30]
t(1;8)(q31.1;p11.2) TRP-FGFR1 At least one case [31]
t(2;8)(q13;p11.2) RANBP2-FGFR1 At least one case [32]
t(2;8)(q37.3;p11.2) LRRFIP1-FGFR1 At least one case [33]
t(7;8)(q22.1;p11.2) CUX1-FGFR1 At least one case [34]
t(8;12)(p11.2;q15) CPSF6-FGFR1 At least two cases [26][35]
t(5;8)(q35;p11) SQSTM1-FGFR1 One case [36]

Characteristic Chromosomal Aberrations / Patterns

A variety of translocations involving 8p11 breakpoint. Secondary cytogenetic abnormalities also occur, most commonly trisomy 21 [2].

Genes and Main Pathways Involved

Normal FGFR1 is a transmembrane protein with an extracellular ligand-binding domain, a transmembrane domain and a cytoplasmic tyrosine kinase domain. In inactive state, FGFR1 presents as monomers in cell membrane. Binding with ligands--the fibroblast growth factors (FGFs), induces dimerization and a conformational change that partially activates the enzymatic activity leading to transphosphorylation of the key tyrosine residue, an increase in enzymatic activity, phosphorylation of additional tyrosines and subsequent phosphorylation of downstream target substrates. The signaling pathways include Ras/MAPK, P13K, PLCÁ and STAT proteins. Fusion proteins with FGFR1 mimic the initial tyrosine kinase activation and thus possess constitutive tyrosine kinase activity to activate multiple signal transduction pathways in myeloid/lymphoid neoplasms [37][38][39][40].

Diagnostic Testing Methods

Diagnosis is based on integration of morphology, immunophenotype, cytogenetics analysis and molecular analysis. Identification of translocations involving FGFR1 and the corresponding fusion genes is diagnostic in the setting of myeloid or lymphoid neoplasm with prominent eosinophilia. Conventional cytogenetic analysis is useful since almost all the translocations or insertions involving FGFR1 have been cytogenetically visible [41][1]. Translocations of FGFR1 and the associated fusion genes can be more specifically detected by two-color fluorescence in situ hybridization (FISH), and reverse transcriptase–polymerase chain reaction (RT-PCR) [16] [29][42].

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

Unlike myeloid/lymphoid neoplasms with PDGFRA or PDGFRB rearrangement, the prognosis for this FGFR1 associated entity is poor even for patient in the chronic phase, due to the high incidence of transformation. There is no established tyrosine kinase inhibitor therapy for myeloproliferative neoplasms with FGFR1 rearrangement. Midostaurin (PKC412) was reported to be effective in one case [43], and interferon has induced cytogenetic response in several cases [4] [44]. Nevertheless, haematopoietic stem cell transplantation should be considered even for patients in chronic phase.

Familial Forms

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Links

FGFR1

References

EXAMPLE Book

  1. Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p129-171.

Notes

*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.

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